This work represents over 13 years of collaboration between the Diabetes Branch and the Institute of Histology and Embryology at the University of Geneva. The initial observations demonstrated that polypeptide hormones are taken up by the cell through a process of receptor-mediated endocytosis similar to other biologically important ligands that bind to cells. In the present study, using election microscopy, we find there is anatomical correlation between the dissociation of (125)I-insulin and its localization on the cell surface. This work has now been extended to include an insulin-resistant cell line that has an abnormal surface which leads to a higher association of ligand to the non-villous portion of the cell surface. Further, receptor-mediated endocytosis also appears to be regulated in hypoinsulinemic states. In both rat and in human type I diabetes there is an inhibition of (125)I-insulin internalization in the hyperglycemic state: the normal state is restored by insulin treatment. The role of intracellular calcium on the endocytotic process, as well as the relationship of stimulators of protein kinase C to internalization of both insulin and unrelated ligands such as transferrin, have been studied also. In addition, the function of the small non-coated invaginations in receptor-mediated endocytosis is being investigated.